Our research on DNA-protein interactions involving restriction endonucleases and the corresponding methylases as the protein component and well define oligonucleotides and competitive inhibitors as the DNA component, has generated exciting possibilities for further work. Large scale isolation procedures for the endonucleases Hpa I and Hpa II have been developed. Both proteins have been chemically and physically characterized. Recently, we have isolated two proteans possessing Hpa II methylase activities. Both of these proteins appear to be related. Purification of Hpa I methylase is presently being investigated. Using chemically synthesized oligonucleotides and Hpa I endonuclease, we have established that the 5-methyl group of thymidine and 2-amino group of guanine are important contact points for the enzyme. In order to probe other contact points, we are presently studying the interaction of several other oligonucleotides and the Hpa I endonuclease.